The striatum participates in many brain functions, in particular in our ability to learn and retain motor skills and in drug reward behaviors. Changes in striatal function are implicated in multiple neuropsychiatric diseases, including drug addiction. Importantly, human genetic studies have linked the neurexin genes to drug addiction predisposition. I present here preliminary data suggesting that neurexin mutant mice display alterations in striatum-dependent behaviors: an enhancement of motor learning and a reduction in cocaine reward, which suggest a mechanistic commonality between the two behaviors and suggest a model system to investigate the noted connection between the human neurexin genes and drug addiction predisposition. I propose experiments to test the hypothesis that alternative splicing at a single exon in the neurexin-3 gene modulates these striatum-dependent behaviors. I also propose to identify the specific brain regions that project to the striatum and are responsible for supplying the behavior-modifying neurexin protein. The goal of this research is to advance our understanding of the role of neurexin alternative splicing in cognitive function and to identify brain circuitry likely relevant to diseases with a striatal dysfunction component, such as drug addiction. Additionally, by defining the function of the neurexin genes in striatum-dependent behaviors, the proposed research will provide insight into the connection between mutations in human neurexin genes and drug addiction predisposition and point to a potential target for therapeutic intervention. PUBLIC HEALTH RELEVANCE: The striatum is a brain structure essential for our ability to plan, learn, and retain new motor skills and is also implicated in drug addiction. This proposal seeks to identify the function of the neurexin genes, which have been implicated in predisposition to drug addiction. The goal of the proposed research is to identify the function of the neurexin genes in striatum-dependent behaviors and to provide insight into the connection between mutations in human neurexin genes and drug addiction predisposition, pointing to a potential target for therapeutic intervention.